Genome-Wide Transcriptional Analysis Reveals Alternative Splicing Event Profiles in Hepatocellular Carcinoma and Their Prognostic Significance.

Yongfu Xiong,Muhammad Riaz,Ji Sun,He Zhou,Zhenbing Lv,Tang Tao,Qiang Li,Weinan Li,Jingdong Li,Jian Xu,Kang Wang,Gang Yang

doi:10.3389/fgene.2020.00879

Abstract

Accumulating evidence indicates an unexpected role of aberrant splicing in hepatocellular carcinoma (HCC) that has been seriously neglected in previous studies. There is a need for a detailed analysis of alternative splicing (AS) and its underlying biological and clinical relevance in HCC. In this study, clinical information and corresponding RNA sequencing data of HCC patients were obtained from The Cancer Genome Atlas. Percent spliced in (PSI) values and transcriptional splicing patterns of genes were determined from the original RNA sequencing data using SpliceSeq. Then, based on the PSI values of AS events in different patients, a series of bioinformatics methods was used to identify differentially expressed AS events (DEAS), determine potential regulatory relationships, and investigate the correlation between DEAS and the patients’ clinicopathological features. Finally, 25,934 AS events originating from 8,795 genes were screened with high reliability; 263 of these AS events were identified as DEAS. The parent genes of these DEAS formed an intricate network with roles in the regulation of cancer-related pathway and liver metabolism. In HCC, 36 splicing factors were involved in the dysregulation of part DEAS, 100 DEAS events were correlated with overall survival, and 71 DEAS events were correlated with disease-free survival. Stratifying HCC patients according to DEAS resulted in four clusters with different survival patterns. Significant variations in AS occurred during HCC initiation and maintenance; these are likely to be vital both for biological processes and in prognosis. The HCC-related AS events identified here and the splicing networks constructed will be valuable in deciphering the underlying role of AS in HCC.

Highlights

Despite great advances in recent decades in screening, diagnosis, and curative surgery, hepatocellular carcinoma (HCC) remains the second leading cause of cancer-related mortality worldwide (Grandhi et al, 2016; Siegel et al, 2018)
Based on their splicing patterns, these alternative splicing (AS) events could be roughly classified into seven types: alternate promoter (AP), mutually exclusive exons (ME), retained intron (RI), exon skipping (ES), alternate acceptor site (AA), alternate terminator (AT), and alternate donor site (AD) (Figure 1A)
We further compared the variance in quantity of AS events and the genes involved between tumor, adjacent paired normal, and unpaired tumor tissues for different splicing patterns

Summary

Introduction

Despite great advances in recent decades in screening, diagnosis, and curative surgery, hepatocellular carcinoma (HCC) remains the second leading cause of cancer-related mortality worldwide (Grandhi et al, 2016; Siegel et al, 2018). The initiation and maintenance of HCC is a complex and regulated process involving the accumulation of numerous genetic changes over decades (Niu et al, 2016; Erkekoglu et al, 2017). These sequential alterations endow normal liver cells with neoplastic ability, enabling uncontrolled growth, and provide potential therapeutic targets and biomarkers. Further understanding of the initiation and maintenance of HCC at the molecular level is crucial to prolonging survival and making individual treatment decisions

Methods

Results

Conclusion